JP2002520356A - Flavonoid-based therapeutic compositions intended for use in treating tumors with cytotoxic agents - Google Patents

Abstract

  (57) [Summary] The present invention provides a therapeutically effective amount of a flavonoid, especially a compound of formula I wherein R₁, R_Two, R_Three, R_Four, R _FiveAnd R₆As defined in claim 2), wherein the composition has activity on the growth of clonogenic cells in tumors. The composition is designed for use in treating a tumor with a cytotoxic agent.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of compounds of the flavonoid type in the treatment of cancer with cytotoxic agents. Cancer is a disorder of somatic genes during which genetic dysfunction worsens as the tumor progresses from a precancerous lesion to a malignant transformation, cancerous tumors become metastatic, and often , Become resistant to cytotoxic drugs. In particular, despite very considerable efforts made in many developed countries through experimental and clinical research programs, mortality from various cancers (solid tumors and hematological neoplasms) has been unacceptably high. Remains high. In many countries, cancer is the second leading cause of mortality, shortly after cardiovascular disease.

For newly diagnosed cancers, the distribution between solid tumors and hematological (bone marrow, blood, lymphoid) neoplasms is that 9 out of 10 cancers are solid tumors Is shown. Unlike what is observed in hematological tumors (successful treatment in 40-90% of blood cell carcinomas), only a few advanced or diffuse solid tumors are the only ones responding to chemotherapy treatment. It is partly for this reason that the overall mortality from cancer increased in the United States between 1973 and 1992.

[0003] This trend has led to the development of new anti-tumor agents, such as taxanes that interfere with microtubule formation.
xane) [paclitaxel and docetaxel] (WP
McGuire et al., AM. Intern. Med., 1989), camptothecin-derived topoisomerase I inhibitors (topotecan and irinotecan), vinorelbine (vinor
elbine) (a new alkaloid derived from periwinkle), gemcitabine (ge
mcitabine), a novel cytotoxic antimetabolite, raltitrexed
Unfortunately, it can only be reversed by the appearance of thymidylate synthase inhibitor) or miltefosine (the first representative of the alkylphosphocholine family) alongside established chemotherapeutic measures. Not sure. These treatments are added as a first choice or as a second choice to agents whose specific activity is now well understood, such as doxorubicin, cisplatin, vincristine, methotrexate, 5-fluorouracil.

[0004] One of the most difficult current problems of anti-cancer chemotherapy is the fact that many populations of malignant cells show considerable resistance to established cytotoxic agents. Most usually, this situation is due to the presence of multiple resistance genes or the frequency of genetic mutations in certain types of tumors. Thus, treatment of cancer is complementary to current approaches and is intended to more conveniently attack the expansion and heterogeneity of tumor burden and the acquisition of "multicytotoxic-drug" resistance. Requires a new approach.

[0005] Among these new approaches, some are already promising. This is the case for induction of apoptosis and inhibition of tumor angiogenesis and metastatic processes, not to refer to gene therapy or immunotherapy. The inventor was interested in a different approach. It has two advantages: 1) increased cytotoxic activity and thus efficacy, and 2) reduced frequency and severity of certain side effects due to lower doses following induction of increased antitumor efficacy. To achieve the reduction, the population of tumor cells was to be more sensitive to baseline anti-cancer treatment.

It has weak anti-tumor potency or lacks this potency, but is first caused by substances that can induce a very significant increase in the cytotoxic activity of known anti-cancer drugs. It is this strategy that supports the discovery of the function of. This first mechanism stimulates the recruitment of clonogenic cells in the tumor, making it more sensitive to conventional treatment with cytotoxic agents, or inhibiting the growth of clonogenic cells, It is the result of the potential of those substances that contribute to tumor regression.

Accordingly, an object of the present invention is to provide flavonoids and, in particular,

Embedded image

Wherein R ₁ , R ₂ , R ₃ and R ₄ are independently selected from H, OH, C ₁ -C ₄ alkoxy and —OCOR ₇ , wherein R ₇ Is a C ₁ -C ₄ alkyl group, at least one of the substituents R ₁ , R ₂ , R ₃ , R ₄ is other than H, and R ₂ and R ₃ together form a methylenedioxy group may form a; -R ₅ is H, OH, is selected from C ₁ -C ₄ alkoxy group and O- glycosyl group; -R ₆ is a cyclohexyl group, a phenyl group, and H, OH, and C ₁ the selected group from -C ₄ alkoxy groups are selected from phenyl groups even 1-3 times substituted; and - two lines of solid and dotted lines, is represented by 'indicates either a double bond or a single bond A compound having an activity on the growth of clonogenic cells selected from the group consisting of at least one antitumor agent selected from cytotoxic agents Which is of use to the processing.

The cytotoxic agents can be used in their conventional doses, and in this case their efficacy is improved or, at lower doses, leads to an increase in their antitumor efficacy. It is also an object of the present invention to provide a therapeutically effective amount of a flavonoid and, in particular, of the formula:

[0010]

Embedded image

Wherein —R ₁ , R ₂ , R ₃ and R ₄ are independently selected from H, OH, C ₁ -C ₄ alkoxy and —OCOR ₇ , wherein R ₇ Is a C ₁ -C ₄ alkyl group, at least one of the substituents R ₁ , R ₂ , R ₃ , R ₄ is other than H, and R ₂ and R ₃ together form a methylenedioxy group may form a; -R ₅ is H, OH, is selected from C ₁ -C ₄ alkoxy group and O- glycosyl group; -R ₆ is a cyclohexyl group, a phenyl group, and H, OH, and C ₁ the selected group from -C ₄ alkoxy groups are selected from phenyl groups even 1-3 times substituted; and - two lines of solid and dotted lines, is represented by 'indicates either a double bond or a single bond The generation of clonogenic cells, by inhibiting their growth and recruitment, or inhibiting their growth, comprising a compound of formula I selected from the group consisting of: By preventing by also relates to compositions with activity against clonogenic cell proliferation.

It is also an object of the present invention to provide a flavonoid for producing a medicament intended to prevent (by inducing or inhibiting) the development of clonogenic cells in a tumor during treatment with at least one cytotoxic agent and In particular, it also relates to the use of a compound of the formula I as defined above. In chemotherapeutic treatment of cancer with cytotoxic agents, flavonoids and especially Formula I
Are administered at the start of chemotherapeutic treatment, at a single dose ingestion or over several days (eg, 5-7 days) at the start of those treatments, and depending on the chemotherapeutic protocol, In between, at the beginning of each cycle of treatment (eg, 2-5 days), it may be administered.

The compound of formula I is conveniently administered by infusion (generally in 1 to 3 hours) at a dose of 5 to 50 mg / kg / day or 200 to 2000 mg / m ² / day. . For maximum effect on the production of clonogenic cells, the flavonoids should be administered in such a way that the tissue concentration obtained is as high as possible.

With regard to the protocol for treatment in the acute phase of treatment, the intravenous route is:-immediate use intended to be administered without modification by intravenous infusion using an infusion line and according to the recommended flow rates Possible infusion solutes (bags, bottles, etc.);-using pharmaceutical solutes known to those skilled in the art, assisted with lyophilisate to be resuspended for intravenous infusion; For example, if the chemotherapeutic treatment prefers oral administration of a cytostatic, it is also possible to schedule an oral route. For this, oral lyophilizates (
Tablets (for oral or perlingual absorption), ready-to-use or fast-acting tablets, oral solutions, suspensions, granules, capsules, and the like.

The compound of formula I is for the most part a natural source compound or a derivative of a natural source compound. For example, the following may be listed: 1) Flavones, such as -quercetin, -4-hydroxyflavone, -6-hydroxyflavone, -7-hydroxyflavone, -5-methoxyflavone, -6-methoxyflavone. -7-methoxyflavone,

-2-cyclohexyl-5-hydroxychromone, -2-cyclohexyl-6-hydroxychromone, -2-cyclohexyl-7-hydroxychromone, wogonin or 5,7-dihydroxy-8-methoxyflavone, -Acacetin or 5,7-dihydroxy-4'-methoxyflavone -pedalitin or 5,6,3 ', 4'-tetrahydroxy-7
-Methoxyflavone,-apigenin or 5,7,4'-trihydroxyflavone,-luteolin or 5,7,3 ', 4'-tetrahydroxyflavone,

Baicalein or 5,6,7-trihydroxyflavone, scutellarein or 5,6,7,4′-tetrahydroxyflavone, fisetin or 7,3 ′ 4,4'-trihydroxyflavonol, -robinetin or 7,3 ', 4', 5'-tetrahydroxyflavonol, -kaempferol or 5,7,4'-trihydroxyflavonol, -kaemferide (Kaempferide) or 5,7-dihydroxy-4'-methoxyflavonol, -morin or 5,7,2 ', 4'-tetrahydroxyflavonol, -myricetin or 5,7,3', 4 ', 5'-pentahydroxyflavonol,

2) Flavonolols, for example:-aromamadendrin or 5,7,4'-trihydroxyflavanolol,-fustin or 7,3 ', 4'-trihydroxyflavanolol -Hydroxyrobinetin or 7,3 ', 4', 5'-tetrahydroxyflavanolol, -taxifolin or 5,7,3 ', 4'-trihydroxyvanolol,

3) Flavanones, for example: -naringenin or 5,6,4'-trihydroxyflavanone, -7,4'-dihydroxyflavanone, -eriodictyol or 5,7,3 ', 4′-tetrahydroxyflavanone, hesperetin or 5,7,3′-trihydroxyflavanone.

Flavone is a preferred compound. The cytotoxic agent may be selected from: i) intercalating agents, in particular daunorubicin, epirubicin, idarubicin, sorbicin, aclarubicin, pirarubicin, acridine, mitozantrone, actinomycin D, eptilinium acetate; ii) platinum derivatives (cisplatin, cisplatin, Carboplatin, oxaliplastin)
An alkylating agent selected from;

Iii) compounds selected from other groups of alkylating agents: cyclophosphamide, ifosfamide, chlormethrin, melphalan,
-Chloramdosyl, estramustine,-busulfan, mitomycin C,-nitrosoureas: BCNU (carmustine), CCNU (lomustine), hotemustine, streptozotocin,-triazine or derivatives: procarbazine, decarbazine,-pipobroman,-ethyleneimine: artretamine, tri Ethylene thiophosphoramide,

IV) compounds selected from other groups of antimetabolites: antifolates: methotrexate, raltitrexide, antipieimidines: 5-fluorouracil (5-FU), cytarabine (Ara-C)
-Anti-purines: purinsol, thioguanine, pentostatin, cladribine,-inducers of cytotoxic nucleoside synthesis: gemcitabine,

V) compounds selected from another group of agents having an affinity for tubulin:-vinca disrupting the mitotic spindle-alkaloids: vincristine, vinblastine, vindesine, navelbine,-mitotic spindle Agents that prevent depolarization of DNA: paclitaxel, docetaxel,-agents that induce DNA fragmentation by inhibiting topoisomerase II: etoposide, teniposide,-topoisomerase I inhibitors that induce DNA degradation: topotecan, irinotecan,

Vi) a fission agent that fragments DNA, such as bleomycin; vii) one of the following compounds: plicamycin, L asparaginase, mitoguazone, decarbazine, viii) anticancer stimulating steroids: medroxyprogesterone, megestrol Ix) anti-cancer estrogenic steroids: diethylstilbestrol, tetrasodium phosphestrol, x) anti-estrogens: tamoxifen, droloxifene, raloxifene, aminoglutethimide, xi) steroidal anti-androgens (excluding cyproterone) Or non-steroidal antiandrogens (flutamide, nilutamide).

In particular, the compounds of the formula I can be combined in all treatments with the following main cytotoxic agents used in multichemotherapy for solid tumors:-alkylating agents: oxazophorin (cyclophosphamide -Ifosfamide, chlorambucil, melphalan),-nitrosoureas,-mitomycin C,-antimetabolites such as methotrexate, 5-FU, Ara-C, capacitor bottles,-agents that interfere with tubulin: vinca alkaloids (vincristine, vinblastine) , Vindesine, navelbine), taxoids (paclitaseser, docetaxel), epipodophyllotoxin derivatives (etoposide, teniposide),-bleomycin,-topoisomerase I inhibitor: topotecan, irinotecan.

Similarly, compounds of formula I may be combined with treatment with major cytotoxic agents used in tumor hematology for the treatment of hematological cancers: Hodgkin's disease: cyclophosphamide, mechlorethamine, chlorambucil, Melphalan, ifosfamide, etoposide, doxorubicin, daunorubicin;-acute leukemia: methotrexate, 6-mercaptopurine, cytarabine, vinblastine, vincristine, doxorubicin, daunorubicin, L-asparaginase;

Non-Hodgkin's malignant lymphoma: mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide, methotrexate, cytarabine, vinblastine, vincristine, etoposide, doxorubicin, daunorubicin, carmustine, lomustine, cisplastin; Lymphocytic leukemia: mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide. The results of pharmacological tests showing the properties of the compounds of the formula I used alone or in combination with cytotoxic agents will be given hereafter.

1—Interaction with clonogenic cell development (stimulation or inhibition of proliferation) ( Clonogenic assay) : The assay used is Hamburger et al., (Science, 1977; 197, 460-463). And Salmon et al., (New England J. Med. 298, 1321-1327). A cell is considered clonogenic if it has the ability to grow and give rise to cell colonies. Human tumor stem cells are cells hidden in neoplastic cells that constitute a given tumor.

[0029] These tumor stem cells are responsible for the process of recurrence that can be observed after surgical resection of the primary tumor, and are also responsible for the formation of metastases. In a tumor or tumor cell line, those clonogenic stem cells may have a different origin in the tumor or tumor cell line under consideration due to the fact that they retain their ability to grow in the absence of any solid support. Different from cells.

In this assay, tumor cells are cultured on a semi-solid support consisting of agar. The only cells that do not require a solid support for growth (ie, MI Daw
Son et al., Cancer Res. 1995: 55, a highly tumorigenic cell designated as "fixed-independent cells"; also, for "clonal expansion", clonogenic cells) It can grow on such agar-based supports. In particular, normal cells ("fixed-dependent cells" according to MI Dawson nomenclature), such as fibroblasts, which grow in an "adherent format" on such media do not survive. Within a tumor cell population cultured on such a support, it is possible that those clonogenic cells (unlimited number of cell divisions and "fixed-independent [clonal] Proliferation "(related to proliferation).

The percentage of tumors or their clonogenic cells in the tumor cell line is between 0.1% and 0.001%
It is. Non-clonogenic cells, which are associated with a limited number of cell divisions, are subject to their proliferation to occur in an "adherent format" (MI Dawson et al., Cancer Res.
According to 1995, 55: 4446-51, it does not grow in this assay because it requires a fixed support for "fixed-dependent [adhesive] growth").

The effect of compounds of formula I on the growth of cell colonies obtained by culturing, for example, the breast cancer lines MCF7 and MXT, and the colorectal line HT-27 on a semi-liquid culture medium called “soft agar” is determined. Was done. On such media, only clonogenic cells, termed "fixed-independent (clonal) cells" by MI Dawson survive,
And proliferate. The proliferation of those cells in such "non-adherent" formation indicates their degree of tumorigenicity. In turn, inhibition of tumor size growth, where large numbers of clonogenic cells are growing, is a sign of enhanced cytotoxic activity. Conversely, this assay can also show that compounds that render tumors incapable of growing, and thus reduce the population of tumor cells, can inhibit clonogenic cell development / proliferation.

The tumor cell lines to be studied are maintained in culture in 25 cm ² Falcon dishes. Then they are trypsinized and the cells are well separated from each other. The percentage of liver cells is determined after trypen blue staining. 5 × 10 ⁴ 〜15 × 10 ¹⁴
A cell suspension at a concentration of individual cells / ml (depending on the cell type under consideration) is prepared in a solution of agar at 0.3%. Next, 200 μl of this suspension are inoculated into a 35 mm diameter petri dish on which is placed a 3 ml base layer consisting of a solution of agar at 0.5%. 200 μl of the cell suspension are covered by a 1.8 ml top layer consisting of a solution of agar at 0.3%.

Next, the dishes are placed in an incubator at 37 ° C., 5% CO ₂ and 70% humidity until processing. The latter is performed about 1-2 hours after inoculation. Compounds to be assayed are prepared at a concentration 100 times higher than desired and 50 μl of their treatment solution is placed on the upper agar layer of its corresponding dish. In this study,
The final concentrations of the products to be assayed are 10 ⁻⁵ , 10 ⁻⁷ and 10 ⁻⁹ .

The dishes are then kept in the incubator for 21 days. Day 21, dishes are RPMI16
Top layer of a solution of MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) at 1 mg / ml, prepared with 40 medium.
Process by placing on 0 μl at 37 ° C. for 3 hours. After this time, the cell colonies are fixed by adding 2 ml formol per dish. twenty four
After fixation of time, the formol is evaporated and stained, and thus the number of cell colonies consisting of cells that are metabolically active and have a surface area of 100 μm ² or more is determined using an inverted microscope Is done.

The average number of clonogenic cell clones, determined for each experimental condition studied, the average number of clonogenic cell clones counted under control conditions and taken to equal 100% Expressed as% of Those values, expressed as% of control conditions, are given in Table 1 below for quercetin.

[0037]

[Table 1]

On the three cell lines MCF7, HT-29 and MXT, quercetin can partially inhibit the growth of clonogenic cells in tumors, ie, the number of colonies obtained under control conditions On the other hand can induce a significant reduction in the number of colonies of those cells (from 20% to 50%) and thus make the tumors from which they are derived more susceptible to conventional treatment with cytotoxic agents To contribute to.

2—Cytotoxic Activity on Non- Clonogenic Cells: “MTT Assay”: The effect of a compound of formula I on non-clonogenic cells is assessed using an MTT calorimeter assay. The principle of the MTT assay is that the yellow product MTT (3- (4
, 5-Dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) based on mitochondrial reduction by metabolically active living cells. The amount of formazan so obtained is directly proportional to the amount of viable cells present in the culture well. This formazan amount is measured by a spectrometer.

The cell line is maintained by monolayer culture at 37 ° C. in a capped dish containing MEM 25 MM HEPES basic medium (minimum required medium). This medium is suitable for the growth of a wide variety of diploid or primary mammalian cells. Next, this medium is
Replenish with the following components: degraded for 1 hour at -56 ° C, 5% FCS (fetal calf serum), -0.6 mg / ml L-glutamine, -200 IU / ml penicillin, -200 µg / ml Streptomycin, and -0.1 mg / ml gentamicin.

The twelve human cancer cell lines used were from the American Type Culture Collection (ATCC
, Rockville, MD, USA). The cell lines are as follows:-Two glioblasts, U-373MG (ATCC code: HTB-17) and U-87MG (
ATCC code: HTB-14), astrocytoma SW1088 (ATCC code: HTB-12), -2 types of non-small cell lung cancer A549 (ATCC code: CCL-185) and A-427 (ATCC)
Code: HTB-53),

Two types of colorectal cancer, HCT-15 (ATCC code: CCL-225) and LoVo (ATCC
Codes: CCL-229), -2 types of breast cancer, T-47D (ATCC code: HTB-133) and MCF7 (ATCC code:
HTB-22), J82 (ATCC code: HTB-1) and T24 (ATCC code: HTB)
-4), PC-3 which is a prostate cancer (ATCC code: CRL-1435).

During the experimental period, 100 μl of a cell suspension containing 20,000-50,000 cells (depending on the cell type used) / ml culture medium are inoculated into flat-bottomed 96-well multi-well plates. And under an atmosphere comprising 5% CO ₂ and at a humidity of 70% at 37 ° C.
Incubate with After 24 hours of incubation, the culture medium is changed to 10 ^-5 to
^Different compounds to be tested at a concentration in the range of ^10-10 M, or different compounds to be tested,
Alternatively, replace with 100 μl of fresh medium containing any of the solvents used to dissolve the product to be tested (control conditions).

After 72 incubations under the above conditions, the culture medium is replaced by 100 μl of a yellowish solution of MTT dissolved in RPMI 1640 at a rate of 1 mg / ml. The microtiter plate was reincubated at 37 ° C. for 3 hours, and then
Centrifuge at 0g for 10 minutes. The yellowish solution of MTT is removed and the blue formazan crystals formed at the cellular level are dissolved in 100 μl of DMSO. Next, the microplate is shaken for 5 minutes.

Thus, the yellow MTT to blue formazan by the cells, which still persists at the end of the experiment
The intensity of the blue color resulting from the conversion of the product was measured at 570 nm and 630 nm corresponding to the wavelengths of formazan and background maximum absorbance, respectively, of the type DYNATECH IMM.
Quantification is performed by spectrophotometry using a machine of UNOASSAY SYSTEM. The software incorporated in the spectrometer calculates the mean value of the optical density and the standard deviation (Std. Dev.) And the standard error of the mean value (SEM).

According to the examples, the control conditions (taken to be equal to 100%) obtained by the non-limiting example with flavonoids, quercetin, against the five tumor cell lines U-373MG, T24, LoVo, MCF7 and A549. The results of the average optical density, expressed as a percentage of the average optical density measured in Table II, will be given in Table II below.

[0047]

[Table 2]

The results show that quercetin has weak antitumor potency. This product, which is non-cytotoxic, elicits an inhibition of the overall cell proliferation of these cell lines only at a concentration of 10-5 M, and this inhibition does not exceed 20%. At other concentrations being assayed, only a few minor effects can be detected.

[0049] 3. Determination of Maximum Tolerated Dose (MTD): Evaluation of the maximum tolerated dose was performed in 4-6 week old B6DF1 / Jico mice.
Compounds were administered via the intraperitoneal route at increasing doses ranging from 2.5 to 160 mg / kg. The value of the MTD (expressed in mg / kg) is determined based on observations of the survival of the animals over a period of 14 days after a single administration of the product under consideration. The progress of the animal's weight is also monitored during this period. If the MTD value is greater than or equal to 160 mg / kg, the MTD value resembles 160 mg / kg with error.

Quercetin is associated with errors with an MTD equal to 160 mg / kg. This result emphasizes that products belonging to the flavonoid family have no direct toxicity and can be used at high tissue concentrations and thus at high doses. Examples of the use of the compounds of formula I in a protocol for mono- or multi-chemotherapy with cytotoxic agents will be given hereinafter.

A. Solid tumor: 1 ° / lung cancer: 1.1 Non-small cell lung cancer (advanced stage):-Recommended protocol (T. Le Chevalier et al., J. Clin. Oncol. 1994;
12: 360-367), by intravenous infusion of the compound of formula I:

[0052]

[Table 3] This treatment will be repeated eight times.

1.2. Small cell lung cancer (advanced stage):-Recommended CAV or VAC protocol (BJ Roth et al., J. Clin. Oncol. 19
92; 10: 282-291) perform flavonoid injection:

[0054]

[Table 4]

This treatment will be repeated six times every 21 days. -Recommended Pt-E protocol (BJ Roth et al., J. Clin. Oncol. 1992; 1
0: 282-291), perform flavonoid injection:

[0056]

[Table 5] Each cycle is repeated every 21 days, and treatment includes 6 cycles.

1.3 Locally Advanced or Metastatic Non-Small Cell Bronchial Cancer: Monochemotherapy:

[Table 6] A treatment possibly comprising a repetition of this 4-week cycle. Gemcitabine / cisplatin combinations:

[0058]

[Table 7] Treatment comprising repeating this cycle every 21 days.

2 ° / BREAST CANCER: -GMF protocol as adjuvant treatment of operable breast cancer (G. Bonnadon
na et al., N. Eng. J. Med. 1976; 294: 405-410).

[Table 8]

Each cycle is repeated every 28 days, and the treatment includes 6 cycles. -AC protocol as adjuvant treatment (B. Fisher et al., J. Clin. On
col. 1990; 8: 1483-1496).

[0061]

[Table 9]

Each cycle is repeated every 28 days, and the treatment includes 4 cycles. Breast Cancer with Metastases: In the FAC protocol (AU Buzdar et al., Cancer 1981; 47: 2537-2542) and its various adaptation protocols, flavonoid injection is performed according to the following scheme (non-limiting):

[0063]

[Table 10]

Each cycle is repeated every three weeks until a new progression of the disease is diagnosed. -In the CAF protocol (G. Falkson et al., Cancer 1985; 56: 219-224):

[0065]

[Table 11]

Each cycle is repeated every 28 days until a new progression of the disease is diagnosed. -In the CMF protocol:

[0067]

[Table 12]

This cycle is repeated every 3-5 weeks, and the treatment includes 6 cycles. -In the CMF-VP protocol:

[0069]

[Table 13]

This treatment will be repeated every four weeks. -In the FFC protocol:

[0071]

[Table 14]

This treatment will be repeated every three weeks. -MMC-VBC protocol (C. Brambilla et al., Tumori, 1989; 75: 141-144)
In):

[0073]

[Table 15]

This treatment will be repeated every 28 days until disease progression is diagnosed. -NFL protocol (SE Jones et al., J. Clin. Oncol. 1991; 9: 1736-173)
In 9):

[0075]

[Table 16]

The treatment involves two cycles 21 days apart and then requires evaluation. Flavonoid injections can also be combined with the treatment of breast cancer with metastases if taxoids are used. -In the treatment in a form having a metastasis possibly resistant to anthracyclines,
Paclitaxel (FA Holmes et al., J. Natl. Cancer Inst. 1991; 83: 1797-1
805):

[0077]

[Table 17]

This cycle is repeated every 21 days until a new progression of the disease is diagnosed. -Docetaxel (C.A.) in locally advanced or metastatic breast cancer that is resistant, or in relapse after cytotoxic chemotherapy (including anthracycline) or during adjuvant treatment. Hudis et al., J. Clin. Oncol.
1996; 14: 58-65):

[0079]

[Table 18]

This cycle is repeated every 21 days during two cycles of treatment or until disease progression appears. - first selection to strengthen for the treatment, in a volume increase protocols by union transplant autologous bone marrow cells and peripheral blood stem cells: - iv infusion of stem cells takes place in D _-1, D ₀ and D ₁ CPB Protocol (WP Peters
Etc., J. Clin. Oncol. 1993; 11: 132-1143):

[0081]

[Table 19]

CTCb protocol in which iv injection of stem cells occurs at D ₀ (K. Antman et al., J. Cl.
in. Oncol. 1992; 10: 102-110):

[0083]

[Table 20]

CTM protocol in which iv injection of hematopoietic stem cells occurs at D ₀ (LE Damon et al.,
J. Clin. Oncol-1989; 7: 560-571 and IC Henderson et al., J. Cellular Bio
chem, 1994 (Suppl 18B): 95):

[0085]

[Table 21]

3 ° / gynecological cancer: 1 Ovarian cancer: -For treatment of ovarian cancer, especially metastatic ovarian cancer: i) PAC protocol (GA Ommura et al., J. Clin. Oncol. 1989; 7: 457-4
65): Flavonoid injection is performed according to the following scheme:

[0087]

[Table 22]

This cycle is repeated every 21-28 days, and the treatment involves 8 cycles. ii) Altretamine protocol according to A. Marietta et al., (Gynecol. Oncol. 1990; 36: 93-96):

[0089]

[Table 23]

The treatment involves two cycles apart for 28 days. iii) Paclitaxel protocol: Flavonoids such as WP McGuire., (
Ann. Intern. Med. 1989; 111: 273-279) can be added to the paclitaxel protocol.

[Table 24]

The treatment involves two of those cycles, including a final assessment, 28 days apart. -For the treatment of metastatic and resistant ovarian cancer, flavonoids can be added to a second selection protocol based on topotecan:

[0092]

[Table 25]

[0093] The treatment is According to P. Kudelka et al. (J. Clin. Oncol. 1996; 14: 1552-1557), include two cycles 21 days apart (including final evaluation). 3. 2. Trophoblastic Tumors: -In patients at low risk, flavonoids are described by H. Takamizawa et al. (Se
min. Surg. Oncol. 1987; 36-44) can be combined with the protocol described by:

[0094]

[Table 26]

[0095] 3. 3 Uterine cancer: -Flavonoids can also be combined with the CAV (or VAC) protocol according to the following scheme:

[0096]

[Table 27]

[0097] Treatment involves repeating this cycle every 21 days. -In the FAP protocol:

[0098]

[Table 28]

Treatment involves repetition of this cycle every 21 or 28 days. 4 ° / testicular and prostate cancer :-Flavonoids can be combined with a protocol for testicular cancer:-BEP protocol:

[0100]

[Table 29]

Treatment includes three cycles, one cycle every 21 days. 5 ° / cancer of the bladder: -Flavonoids can be combined with CISCA2 (also called PAC) protocol:

[0102]

[Table 30]

The cycle is repeated every three weeks. -MVAC protocol (CN Sternberg et al., J. Urol. 1988; 139: 461-469
In):

[0104]

[Table 31]

This cycle is repeated every two to four weeks for a minimum of two cycles. 6 ° / nasopharyngeal cancer / head and neck cancer:-Flavonoids can be effectively combined with the multichemotherapy protocols used to treat those cancers: 6.1 Nasopharyngeal cancer:-ABVD protocol:

[0106]

[Table 32]

Treatment includes 1 to 6 cycles repeated at the rate of 1 cycle every 4 weeks. 6.2 Head and neck cancer with metastases:-Pt according to the DVAL Study Group (New Engl. JM 1991; 324: 1685-1690).
-In the FU protocol (for said nasopharyngeal carcinoma):

[0108]

[Table 33]

Treatment includes two cycles, one cycle every three weeks. 7 ° / soft tissue sarcoma: -Flavonoids can be introduced in one protocol, such as the CYVADIC protocol:-HM Pinedo et al. (Cancer 1984; 53: 1825) according to:

[0110]

[Table 34]

Treatment involves the repetition of this cycle every four weeks during the first two cycles.
Hormone-resistant prostate cancer with 8 ° / metastasis : V according to GR Hudis et al. (J. Clin. Oncol. 1992; 10: 1754: 1761).
In the BL-estramustine protocol:

[0112]

[Table 35]

The treatment cycle lasts 6 weeks and is followed by a free period of 2 weeks. 9 ° / germ cell carcinoma: i) For tumors with favorable prognosis:-Pt according to GJ Bosl et al. (J. Clin. Oncol. 1988; 6: 1231-1238).
E protocol:

[0114]

[Table 36]

Treatment includes four cycles, one cycle every 21 or 28 days. ii) For tumors with metastases:-SD Williams et al. (P according to N. Eng. J. Med. 1987; 316: 1435-1440).
EB protocol:

[0116]

[Table 37] Treatment includes four cycles, one cycle every 21 days. 10 ° / kidney cancer:-Metastatic kidney cancer: Flavonoids are described by MJ Wilkinson et al. (Cancer 1993; 71: 3
601-3604) can be introduced into the protocol described by:

[0117]

[Table 38]

The treatment involves two cycles, separated by 28 days. -Nephroblastoma: Flavonoids can be introduced during the DAVE protocol:

[0119]

[Table 39]

Treatment includes one cycle every 3 to 4 weeks. 11 ° / Gastrointestinal cancer: 11.1 Esophageal cancer: -Flavonoids can be introduced during the EAP protocol:

[0121]

[Table 40]

This cycle is repeated every 3-4 weeks. 11.2 Gastric cancer:-For advanced and / or metastatic gastric cancer:-EAP protocol (P. Preusser et al., J. Clin. Oncol. 1989; 7: 1310):

[Table 41]

The treatment is given at a rate of one cycle every 28 days. -FAMtx protocol according to JA Wils et al. (J. Clin. Oncol. 1991; 89: 827):

[0124]

[Table 42]

The treatment involves two cycles, initially 28 days apart. -For certain diseases, this protocol or a variant thereof (conversion of epirubicin and doxorubicin) can be used according to the following scheme:

[0126]

[Table 43]

12 ° / colorectal cancer: -Flavonoids are introduced during the protocol for FU-Levamisole adjuvant treatment of colorectal cancer according to CG Moertel et al., N. Eng. J. Med. 1990; 322: 352. Can be:

[0128]

[Table 44]

The 5-FU bolus treatment was repeated for 52 weeks, each week, following the D ₁ -D ₅ induction period;
The treatment with the flavonoids is repeated in the same rhythm on the day of the 5-FU bolus and then on the second day following. For treatment of metastatic, colorectal cancer that is resistant to treatment with -5-fluorouracil (5-FU): ML Rothenberg et al. (J. Clin. Oncol. 1996; 14: 1128-1135). According to:

[0130]

[Table 45]

The treatment involves two cycles, 42 days apart. 13 ° / Kaposi's sarcoma: -Flavonoids use anthracyclines incorporated into liposomes 2
Species protocols: i) PS Gill et al., (J. Clin. Oncol. 1995; 13: 996-1003) and CA Pr.
The protocol described by esant et al. (Lancet 1993; 341: 1242-1243):

[0132]

[Table 46]

Treatment includes two cycles repeated 28 days apart before evaluation of efficacy. ii) M. Harrison et al. (J. Clin. Oncol. 1995; 13: 914-920) protocol:

[0134]

[Table 47]

Treatment includes two cycles repeated 28 days apart before evaluation of the effect. 14 ° / metastatic melanoma: -Flavonoids can also be introduced into a combined protocol for treatment of metastatic malignant melanoma:-DTIC / TAM protocol: G. Cocconi et al. (N. Rng. J . Med. 1992; 327: 51
According to 6), the treatment involves 4 cycles of repetition at a rate of 1 cycle every 21 days according to the following scheme:

[0136]

[Table 48]

Treatment includes four cycles, with one cycle every 21 days. 15 ° / neuroendocrine carcinoma: -Flavonoids can be combined with the protocol described by CG Moertl et al. (Cancer 1991; 68: 227):-Pt-E protocol:

[0138]

[Table 49]

[0139] Treatment includes two cycles repeated every 28 days. 16 ° / pancreatic cancer:-Advanced stage pancreatic adenocarcinoma: Flavonoids include M. Moore et al. (Proc. Am. Soc
Clin. Oncol. 1995; 14: 473) can be combined with gemcitabine treatment:

[0140]

[Table 50] B. Oncohematology: 1 ° / Acute leukemia in adults: 1.1 Acute lymphoblastic leukemia: 1.1.1 Linker protocol: The flavonoids are prepared according to the following scheme using the Linker protocol (induced and intensive chemotherapy: CA Linker etc. Blood 1987; 69: 1242-1248 and C.A.
Linker et al. Blood 1991; 78: 2814-2822) can be added: i) Induced chemotherapy:

[0141]

[Table 51]

Ii) Intensified chemotherapy (treatment A):

[Table 52]

Intensive treatment A comprises 4 consecutive cycles, eg cycles as described above = cycles 1, 3, 5 and 7. iii) Consolidation chemotherapy (treatments B and C): The following therapies correspond to consolidation cycles 2, 4, 6 and 8 (therapy B) and 9 (therapy C) as described by CA Linker and others:

Treatment B:

[Table 53]

Treatment C:

[Table 54]

1.1.2 Hoelzer Protocol: Flavonoids were prepared according to the following scheme according to the multi-chemotherapy protocol (D. Hoelz
er, etc., Blood 1984; 64: 38-47, C. Hoelzer, etc., Blood 1988; 71: 123-13.
1) may be added to the cytotoxic agent:

I) Induced chemotherapy / period 1:

[Table 55]

Ii) Induction Chemotherapy / Period 2: Period 2 of induction can be performed as follows:

[Table 56]

Iii) Re-induced chemotherapy / period 1:

[Table 57]

Iv) Re-induced chemotherapy / period 2:

[Table 58]

1.2 Acute Myeloid Leukemia: 1.2.1 Treatment of Adults of Any Age: Flavonoids are described by RO Dilleman et al. (Blood, 1991, 78: 2520-2526), ZA
Arlin et al. (Leukemia 1990; 4: 177-183) and PH Wiernik et al. (Blood 19
92; 79; 313-319) can be added to a process incorporating a standard dose of cytarabine as previously described according to the following scheme:

[0152]

[Table 59]

1.2.2 Treatment of Adults Under the Age of 60: i) Induction Chemotherapy: This induction cycle consists of cytarabine (cytarabine) at high doses according to the following scheme:
rabine) incorporates administration:

[0154]

[Table 60]

To reduce the risk of CNS toxicity in the phenomenon of renal failure, LEDamon et al.
Leukemia 1994; 8: 535-541), GL Phillips et al. (Blood 1991; 77: 1429-14).
35) and G. Smith et al. (J. Clin. Oncol. 1997; 15: 833-839) to adjust cytarabine dosage for creatinine clearance. ii) Intensified chemotherapy: The cycles described hereafter are based on RJ Mayer et al., N. Engl J. Med. 1994;
331: 896-903, will be repeated eight times, at the rate of one cycle every 4-6 weeks:

[0156]

[Table 61]

Iii) Intensified chemotherapy (with high dose of cytarabine): The cycle described hereafter is repeated twice and GL Phillips et al.
(Blood 1991; 77: 1429-1435); SN Wolff et al. (J. Clin. Oncol. 1989; 7:12
60-1267); RJ Mayer et al. (N. Engl J. Med. 1994; 331: 896-903) adapted:

[0158]

[Table 62]

1.2.3 Treatment of Adults Age 60 or Older: Flavonoids can then be added to intensive chemotherapy protocols: i) RO Dilman et al. (Blood 1991; 78: 2520-2526), ZA Arlin etc. (Le
ukemia 1990; 4: 177-183), PH Wiernik et al. (Blood 1992; 79: 313-319):

[0160]

[Table 63]

Ii) According to R. J. Meyer et al. (N. Engl. J. Med. 1994; 331: 896-903):

[Table 64]

Iii) CA Linker et al. (Blood 1993; 81: 311-318), N. Chao et al. (Blood
1993; 81: 319-323) and AM Yeager et al. (N. Eng. J. Med. 1986; 315: 145)
According to -147), this protocol is implemented in bone marrow transplantation (D ₀ autologous)
Including:

[0163]

[Table 65] Or

[0164]

[Table 66]

Iv) PJ Tutscha et al. Blood 1987; 70: 1382-1388, FR Applebaum et al.
For HLA-compatible allogeneic bone marrow transplantation according to Ann. Int. Med. 1984; 101: 581-588:

[0166]

[Table 67]

2 ° / Adult Chronic Leukemia: 2.1 Chronic Myeloid Leukemia: In the myeloblast phase, flavonoids are described by CA Koller et al. (N. Engl.
Med. 1986; 315: 1433-1438) can be added to the HU-Mith treatment:

[0168]

[Table 68]

2.2. Chronic lymphocytic leukemia: 2.2.1 FCG-CLL protocol: Flavonoids are Kimby et al. (Leuk. Lymphoma 1991; 5 (Suppl.) 93-96)
And to the “pulsed chlorambucil” combination as described by FCGCLL (Blood 1990; 75: 1422-1425):

[0170]

[Table 69]

2.2.2 Fludarabine-CdA protocol: HG Chun et al. (J. Clin. Oncol. 1991; 9: 175-188), MJ Keating et al.
(Blood 1989; 174: 19-25 / J. Clin. Oncol. 1991; 9: 44-49) and A. Saven et al. (J. Clin. Oncol. 1995; 13: 570-574):

[0172]

[Table 70]

3 ° / lymphoproliferative disease: 3.1 Hodgkin's disease: Flavonoids can be incorporated into multichemotherapy protocols conventionally used for treatment of Hodgkin's lymphoma: 3.1.1 AVDB protocol: G Bonnadonna et al. (Cancer Clin. Trials 1979; 2: 217-226) and GP Can
ellos et al. (N. Engl. J. Med. 1993; 327: 1478-1484):

[0174]

[Table 71]

The treatment involves 6 to 8 cycles, one cycle every 28 days. 3.1.2 MOPP / ABVD Protocol: G. Bonnadonna et al. (Ann. Intern. Med. 1986; 104: 739-746) and GP Can
(N. Engl. J. Med. 1993; 327: 1478-1484): The MOPP protocol is changed every 28 days by the ABVD protocol (eg, 3.1.1), and treatment is 6 cycles. Includes: MOPP Protocol:

[0176]

[Table 72]

3.1.3 Stanford V Protocol: According to N.L. Bartlett et al. (J. Clin. Oncol. 1995; 13: 1080-1088):

[0178]

[Table 73]

Treatment includes three cycles, one cycle every 28 days. 3.1.4 EVA Protocol: GP Canellos et al. (Proc. Am. Soc. Clin. Oncol. 1991; 10: 273):

[0180]

[Table 74]

The treatment includes 6 cycles, with one cycle every 28 days. 3.1.5 B-CAVe Protocol: According to W.G. Harker et al. (Ann. Intern. Med. 1984; 101: 440-446):

[0182]

[Table 75]

The treatment includes eight cycles, one cycle every 28 days. 3.2 Non-Hodgkin's lymphoma: 3.2.1 Non-Hodgkin's lymphoma with a low degree of malignancy: i) CVP protocol: CM Bagley et al. (Ann. Intern. Med. 1972; 76: 227-234) and CS Portlo
ck et al. (Blood 1976; 47: 747-756).

[0184]

[Table 76]

This cycle is repeated every 21 days until the maximum response. ii) I-COPA protocol: according to RV Smalloy et al. (N. Eng. J. Med. 1992; 327: 1336-1341):

[0186]

[Table 77]

[0187] The treatment involves a pro-rated 8-10 cycles, one cycle every 28 days. iii) Fludarabine-CdA protocol: P. Solol-Celigny et al. (Blood 1994; 84 (Supp. 1): 383a), H. Hoeschster et al. (Blood 1994; 84 (Suppl. 1): 564a) and AC Kay ( J.
According to Clin. Oncol. 1992; 10: 371-377):

[0188]

[Table 78]

For fulglycin, each cycle is repeated every 28 days; for cladribine, each cycle is repeated every 35 days. 3.2.2 Non-Hodgkin's lymphoma with moderate malignancy: i) CHOP or CNOP protocol: EM McKelvey et al. (Cancer 1976; 38: 1484-1493), JO Armitage et al.
J. Clin. Oncol. 1984; 2: 898-902), S. Paulovsky et al. (Ann. Oncol. 1992;
3: 205-209):

[0190]

[Table 79]

Mitoxantrone (N) may even be used to replace doxorubicin (CNOP protocol) in patients older than 60 (dose: iv at D ₁ of each cycle)
12 mg / m ² as a bolus). Treatment with the CHOP or CNOP protocol involves 6-8 cycles, one cycle every 21 days. ii) MACOP-B protocol: (Ann. Intern. Med. 1985; 102: 596-602) and IA Cooper et al. (J. Clin. Oncol. 1994; 12: 769-778):

[0192]

[Table 80]

This treatment protocol extends for 12 weeks and corresponds to one cycle. iii) VACOP-B protocol: According to J.M. Connor et al. (Proc. Ann. Soc. Clin. Oncol. 1990; 9: 254):

[0194]

[Table 81]

Each cycle lasts 12 weeks. iv) m-BACOD / M-BACOD protocol: MA Shipp et al. (Ann. Int. Med. 1986; 140: 757-756) and AT Skarin et al. (J. Clin. OnCol. 1983; 1: 91-98). by:

[0196]

[Table 82]

The treatment includes 10 cycles, one cycle every 21 days. v) ProMACE / CytaBOM protocol: D.L. Longo et al. (J. Clin. Oncol. 1991; 9: 25-38):

[0198]

[Table 83]

The treatment involves 6-8 cycles, one cycle every 14 days.
3.2.3 Non-Hodgkin's lymphoma with low or moderate malignancy: i) ESHAP treatment protocol: WS Velasquez et al. (J. Clin. Oncol. 1994; 12: 1169-1176); Or in the most important processing failure phenomenon:

[0200]

[Table 84]

The treatment involves 6 cycles, with one cycle every 28 days. ii) MINE treatment protocol: In the phenomenon of relapse or most important processing failure according to F. Cabanillas et al. (Semin. Oncol. 1990; 17 (Suppl. 10): 28-33):

[0202]

[Table 85]

This cycle is repeated every 21 days. 3.3 Non -Hodgkin lymphoma: Burkitt lymphoma, small-cell lymphomas, lymphocytic MeHoso cells lymphoma: 3.3.1 Magrath Protocol: flavonoids, may be combined with Magrath protocols according to the following scheme: i) Cycle 1: IT Magrath According to (Blood 1984; 63: 1102-111):

[0204]

[Table 86]

Ii) Cycles 2-15: According to I.T. Magrath et al. (1984):

[0206]

[Table 87]

The treatment involves 14 cycles, one cycle every 28 days. 3.4 Waldenstrom macroglobulinemia: 3.4.1 CVP protocol: MA Dimopoulous et al. (Blood 1994; 83: 1452-1459) and CS Portlock et al. (Blood 1976; 47: 747-756). According to CPV protocol:

[0208]

[Table 88]

[0209] Treatment is continued indefinitely (one cycle every 21 days). 3.4.2 Fludarabine-CdA protocol: HM Kantarjian et al. (Blood 1990; 75: 1928-1931) and MA Dinopoulous
According to (Ann. Intern. Med. 1993; 118: 195-198):

[0210]

[Table 89] Or

[0211]

[Table 90]

Treatment includes 6-12 cycles 28 days apart for fludarabine and 2 cycles for cladribine or 28 days apart. 3.5 Multiple Myeloma: 3.5.1 MP Protocol: Alexanian et al. (JAMA 1969; 208: 1680-1685), A. Belch et al. (Br. J. C
ancer 1988; 57: 94-99) and F. Mandelli et al. (N. Engl. J. Med. 1990; 322: 1
430-1434):

[0213]

[Table 91] Or

[0214]

[Table 92]

Treatment includes at least 12 cycles, with one cycle every 4-6 weeks. 3.5.2 VAD Protocol: According to B. Barlogie et al. (N. Engl. J. Med. 1984; 310: 1353-1356):

[0216]

[Table 93]

3.5.3 MP / Interferon-α Protocol: According to O. Osterborg et al. (Blood 1993; 81: 1428-1434):

[Table 94]

Treatment involves an infinite number of repetitions of this cycle, at a rate of one cycle every 42 days. 3.5.4 VCAP or VBAP protocol: According to SE Salmon et al. (J. Clin. Oncol. 1983; 1: 453-461): VCAP protocol:

[0219]

[Table 95]

VBAP protocol: Cyclophosphamide, replaced by carmustine (BCNU), the rest are identical:

[0221]

[Table 96]

C. Childhood Tumors-Pediatric Oncology: Flavonoids also have antitumor effects, while simultaneously reducing the severity of side effects due to their effects on clonogenic cell recovery and metabolism, and the potential for lower active doses. To improve the effect, it can be incorporated into a multi-chemotherapy protocol for the treatment of pediatric tumors. 1 ° / Ewing Endoma / Early Neuroectodermal Tumor: Flavonoids were prepared using the VCR-Doxo-CY-Ifos-Mesna-E protocol (ED Berger
t., J. Clin. Oncol. 1990; 8: 1514-1524; WH Meyer, etc., J. Clin.
Oncol. 1992; 10: 1737-1742).

[0223]

[Table 97]

Therapy involves 6-10 of their cycles, depending on the initial severity of the sarcoma and the strength of the response. 2 ° / childhood acute lymphoblastic leukemia: 2.1 Induced chemotherapy (D ₁ -D _-30 ). Flavonoids are recommended protocols (PS Gaynon et al., J. Clin. Onc
d., 1993; 11: 2234-2242; J. Pullen et al., J. Clin. Oncol. 1993; 11: 2234.
-2242; J. Pullen et al., J. Clin. Oncol. 1993; 11: 839-849; VJ Land et al., J. Clin. Oncol. 1994; 12: 1939-1945):

[0225]

[Table 98]

Depending on the results of the spinal cord test, addition into the fortification phase is dependent on D _{28 of} the treatment protocol.
Done in 2.2 Intensification / Maintenance Chemotherapy: Flavonoids can be maintained according to the following scheme according to the maintenance protocol (PS Gaynon et al., J. Clin. Oncol. 1993; 11: 2234-2242; J. Pullen et al., J. Clin. Onco
l. 1993; 11: 839-849; VJ Land et al., J. Clin. Oncol. 1994; 12: 1939-1
945) Can be introduced during:

[0227]

[Table 99]

3 ° / Childhood acute myeloid leukemia: Flavonoids are added to the induction and enhancement / maintenance protocol according to the following scheme: 3.1 Induced chemotherapy: Ravindranath et al., J. Clin. Oncol. 1991; 9: 527-580; ME Nesbit et al., J. Clin. Oncol. 1994; 12: 127-135; RJ Wells et al., J. Clin. Oncol.
According to .1994; 12: 2367-2377:

[0229]

[Table 100]

[0230] This cycle is repeated from D _28. 3.2 Intensification / Maintenance Chemotherapy: Ravindranath et al., J. Clin. Oncol. 1991; 9: 527-580; ME Nesbit et al., J. Clin. Oncol. 1994; 12: 127-135; RJ Wells et al., J. Clin. Oncol.
According to .1994; 12: 2367-2377:

[0231]

[Table 101]

4 ° / Childhood Hodgkin's disease: Flavonoids are described by EA Gehan et al. (Cancer 1990; 65: 1429-1437), SP Hunger.
(J. Clin. Oncol. 1994; 12: 2160-2166) and MM Hudson et al. (J. Clin.
Oncol. 1993; 11: 100-108) can be added to the MOPP-ABVD protocol:

[0233]

[Table 102]

This cycle is repeated six times, one cycle every eight weeks, and
Includes 6 cycles. If an autologous bone marrow graft (autograft) is ordered, R. Chopra et al. (B
lood 1993; 81: 1137-1145), C. Wheeler et al. (J. Clin. Oncol. 1990; 8: 64)
8-656) and R.J. Jones et al. (J. Clin. Oncol. 1990; 8: 527-537)
The CVB protocol used can be used according to the following scheme (the allograft is D ₀ Taken at):

[0235]

[Table 103]

5 ° / Childhood Lymphoblastic Lymphoma: Flavonoids may also be induced by chemotherapy (such as AT Meadown., J. Clin. Oncol. 1
989; 7: 92-99, C. Patte et al., Med. Ped. Oncol. 1992; 20: 106-113, and A
. Reiter et al., J. Clin. Oncol. 1995; 13: 359-372) and maintenance chemotherapy protocols: 5.1 Induced chemotherapy:

[0237]

[Table 104]

5.2 Maintenance Chemotherapy: According to the following scheme:

[0239]

[Table 105]

The treatment involves 10 cycles. 6 ° / pediatric neuroblastoma: The recommended Doxo-E-Cy-Pt multichemotherapy protocol is RP Castleberry et al. (J. Clin. Oncol. 1992; 10: 1299-1304), A. Caraventa et al. (J. Clin. O
ncol. 1993; 11: 1770-1779) and DC West et al. (J. Clin. Oncol. 1992; 11:
84-90) adapted from:

[0241]

[Table 106]

Evaluation of therapeutic response is performed 9 weeks later to determine based on approaches such as surgical amputation, radiation therapy or new chemotherapy. 7 ° / pediatric osteosarcoma: Flavonoids are described by M. Hudson et al. (J. Clin. Oncol. 1990; 8: 1988-1997), P.
A Meyers (J. Clin. Oncol. 1992; 10: 5-15) and VHC Bramwell etc. (J. C.
lin. Oncol. 1992; 10: 1579-1591) can be added to the Doxo-Pt-Mtx-Lcv protocol as described by:

[0243]

[Table 107]

8 ° / Child Rhabdomyosarcoma: Vcr-Dact-Cy-Mesna protocol (H. Maurer et al., Cancer 1993; 71: 1904-
1922 and LR Mandell et al., Oncology 1993; 7: 71-83) can include iv injection of flavonoids according to the following scheme:

[0245]

[Table 108]

At the end of the ninth week of treatment, efficacy should be evaluated to determine based on subsequent criteria (surgery, radiotherapy, continuation of chemotherapy). 9 ° / Wilms tumor in childhood: GJ D'Angio et al. (Cancer, 1989; 64: 349-360) and DM Green et al. (J. Cli
n. Oncol. 1993; 11: 91-95) in the Vcr-Dact protocol as described in:

[0247]

[Table 109]

This protocol is initiated after surgical resection. For autologous bone marrow transplants (autografts) according to A. Garaventar et al. (Med. Pediatr. Oncol. 1994; 22: 11-14), the E-Thio-Cy protocol can be modified as follows:

[0249]

[Table 110] Bone marrow graft, taken at D _0.

[Procedure amendment]

[Submission date] January 24, 2001 (2001.1.14)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Correction contents]

[Claims]

Embedded image Wherein -R ₁ , R ₂ , R ₃ and R ₄ are independently selected from H, OH, C ₁ -C ₄ alkoxy and —OCOR ₇ , wherein R ₇ is C ₁ A C ₄ alkyl group, at least one of the substituents R ₁ , R ₂ , R ₃ , R ₄ is other than H, and R ₂ and R ₃ together form a methylenedioxy group at best; -R ₅ is H, OH, is selected from C ₁ -C ₄ alkoxy group and O- glycosyl group; -R ₆ is cyclohexyl, phenyl and H, OH, and C ₁ -C _4, Selected from phenyl groups substituted even one to three times by a group selected from alkoxy groups; and-the solid and dotted double lines represent either double or single bonds]. A composition comprising a therapeutically effective amount of a compound selected from (excluding naringenin).

Embedded image Wherein -R ₁ , R ₂ , R ₃ and R ₄ are independently selected from H, OH, C ₁ -C ₄ alkoxy and —OCOR ₇ , wherein R ₇ is C ₁ A C ₄ alkyl group, at least one of the substituents R ₁ , R ₂ , R ₃ , R ₄ is other than H, and R ₂ and R ₃ together form a methylenedioxy group at best; -R ₅ is H, OH, is selected from C ₁ -C ₄ alkoxy group and O- glycosyl group; -R ₆ is cyclohexyl, phenyl and H, OH, and C ₁ -C _4, Selected from phenyl groups substituted even one to three times by a group selected from alkoxy groups; and-a double line consisting of a solid line and a dotted line indicates either a double bond or a single bond]. Use of compounds selected from the class (excluding naringenin).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) C07D 311/32 C07D 311/32 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, I, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV , MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Kiss, Robert Belgian, Be-1070 Brussels, Rue du Renik 808, Sepe 620, Laboratoire distology, Facult de Medicine, Univercity De Brussels (72) Inventor Friedman, Armin France, F-94701, Maison Alfort, Abnu du Profésadeur Cadio, 19, Laboratoire Er. Lafon F-term (reference) 4C062 EE50 EE54 4C086 AA01 AA02 BA08 MA01 MA04 NA14 ZB26

Claims (10)

[Claims] 1. having activity on the growth of clonogenic cells in a tumor,
And a composition comprising a therapeutically effective amount of a flavonoid. 2. having activity on the growth of clonogenic cells in a tumor,
And the following formula: Wherein -R ₁ , R ₂ , R ₃ and R ₄ are independently selected from H, OH, C ₁ -C ₄ alkoxy and —OCOR ₇ , wherein R ₇ is C ₁ A C ₄ alkyl group, at least one of the substituents R ₁ , R ₂ , R ₃ , R ₄ is other than H, and R ₂ and R ₃ together form a methylenedioxy group at best; -R ₅ is H, OH, is selected from C ₁ -C ₄ alkoxy group and O- glycosyl group; -R ₆ is cyclohexyl, phenyl and H, OH, and C ₁ -C _4, Selected from phenyl groups substituted even one to three times by a group selected from alkoxy groups; and-the solid and dotted double lines represent either double or single bonds]. A composition comprising a therapeutically effective amount of a compound selected from: 3. The composition of claim 2, wherein said flavonoid is a flavone. 4. The composition of claim 1, wherein said flavonoid is quercetin. 5. Use of a flavonoid for the manufacture of a medicament intended to prevent the development of clonogenic cells in a tumor during the treatment of the tumor with at least one cytotoxic agent. 6. A method for producing an agent intended to prevent clonogenic cell development in a tumor during treatment of the tumor with at least one cytotoxic agent, Wherein -R ₁ , R ₂ , R ₃ and R ₄ are independently selected from H, OH, C ₁ -C ₄ alkoxy and —OCOR ₇ , wherein R ₇ is C ₁ A C ₄ alkyl group, at least one of the substituents R ₁ , R ₂ , R ₃ , R ₄ is other than H, and R ₂ and R ₃ together form a methylenedioxy group at best; -R ₅ is H, OH, is selected from C ₁ -C ₄ alkoxy group and O- glycosyl group; -R ₆ is cyclohexyl, phenyl and H, OH, and C ₁ -C _4, Selected from phenyl groups substituted even one to three times by a group selected from alkoxy groups; and-a double line consisting of a solid line and a dotted line indicates either a double bond or a single bond]. Use of compounds selected from the class. 7. Use according to claim 6, wherein said flavonoid is a flavone. 8. Use according to claim 5, wherein the compound of the formula is quercetin. 9. A method for chemotherapeutic treatment of a tumor in a patient with at least one cytotoxic agent, comprising administering a therapeutically effective amount of a flavonoid during treatment with the cytotoxic agent. 10. The method of claim 9, wherein said flavonoids are administered at the beginning of said chemotherapy treatment and at the beginning of each cycle of said chemotherapy treatment.